Abstract Obstructive sleep apnea (OSA) is a growing sleep-related breathing disorder affecting up to 10% of the adult population compared to 2-4% in 1993. OSA patients undergo recurrent upper airway collapse due to suppression of upper airway dilator muscle activity during sleep, and thus suffer from repeated hypoxia, frequent stressful arousals sleep deprivation. OSA has a major clinical impact due to its cardiovascular, metabolic and neurocognitive sequelae. Brainstem noradrenergic (NA) system plays a critical role in the pathology of OSA by maintaining the tonus of upper airway (UA) muscles that keep airway open. The NA system is also a major contributor to the neuronal mechanisms that lead to a loss of the UA muscle tone during rapid-eye-movement (REM) sleep. However, there is limited information regarding functional relationship between particular groups of NA neurons and UA muscles. Most importantly, there was no attempt to assess relative contribution of each of the brainstem NA group in depression of UA muscle activity during NREM and REM sleep. In the proposed research project, we will use a combination of techniques: chronic intermittent hypoxia (CIH), a major pathogenic factor in OSA, and a novel molecular-genetic technology that will allow a cell-type- specific activation or inhibition of NA neurons in each of the brainstem groups (A1, A2, A5, Locus Coeruleus, SubC, and A7) while recording activity of the genioglossus (GG) muscles during sleep-wake cycles in behaving DBH-Cre transgenic mice. We will 1) determine the functional relationship between activity of these NA groups and GG muscle activity and effect of CIH on this relationship; 2) quantify the relative contribution of each of the NA neuronal groups to the depression of GG activity during natural NREM and REM sleep in CIH- and sham- treated mice; 3) identify the pattern of efferent connections of each of the NA groups to and within the hypoglossal nucleus, a major nucleus innervating UA muscles including the GG muscle, and to other medullary sites important for the control of upper airway muscle tone; and 4) determine the magnitude of CIH-induced sprouting of axonal terminals within the hypoglossal nucleus that originate from different NA nuclei. The proposed work will rank the brainstem NA neuronal groups according to their involvement in the control of UA muscles in CIH and control mice. Importantly, it will quantitatively characterize the contribution of each of the NA group to depression of GG muscle activity during NREM and REM sleep in mice subjected to CIH or sham exposure. Therefore, results of this study will fill a major gap in our understanding of the underlying mechanisms of OSA pathogenesis and may help in designing pharmacological or genetic treatments to prevent OSA.